1. Anticonvulsant Pharmacokinetics Dennis Mungall, Pharm.D. Director, Virtual Education, NTPD Associate Professor Pharmacy Practice Ohio State University College of Pharmacy

2. Absorption of Phenytoin Phenytoin sodium is 92% phenytoin The time to peak is 3-12 hours after single dose of a capsule or tablet Dilantin Kapseals are the only formulation that has absorption characteristics necessary for once daily dosing Oral absorption fo Dilantin approaches 100%

3. Oral preparations of Phenytoin

4. Time to Peak Cp Dose (mg) 400 800 1600 Peak Time ( hrs) 8.4 13.2 31.5

5. Parenteral Administration of Phenytoin Gugler R et al. Clin Pharmac.Ther 1976; 135-42

6. Distribution of Phenytoin Following IV phenytoin distribution to tissues occurs in 30-60 minutes Distribution to the brain is very rapid The mean volume of distribution is comparable to total body water: 0.6-0.7 Liters/kg. Phenytoin binds primarily to albumin, with approximately 10 percent of the drug normally unbound.

7. Conditions that lead to decreased protein binding of Phenytoin Decreased In serum Albumin Burns Hepatic cirrhosis Nephrotic syndrome Pregnancy Cystic Fibrosis Decreased in affinity of binding to albumin Renal Failure Jaundice Other medications

8. Adjustment of Total Phenytoin concentration for Albumin Cnormal = Cobserved/(0.2*alb+0.1)

9. Metabolism Elimination of phenytoin occurs primarily by biotransformation to inactive hydroxylated metabolites. The process of phenytoin elimination is saturable Thus, increases in dose lead to disproportionate increases in phenytoin concentration

10. Variation in Phenytoin Dose/cp Lund L. Bilogical Effects of Drugs. University Park Press 1972;227-39

11. Demonstration of Dose/CP nonlinearity for Phenytoin Richens A., Dunlop A. Lancet 1975;2:247-48

12. Steady State Concentration Vmax= maximum rate of phenytoin metabolism in mg/day Km: the concentration at which the rate of metabolism is half maximal ( mg/liter Css= Km-Dose(day)/Vmax-Dose(day)

13. Saturation Pathway for Phenytoin

14. Time to steady state based on dosing rate

15. Time to 90% of SS as a function of Vmax and Km

16. Equation for Time to 90% SS T90% =(Km*Vd)/(Vm-Dose) * (2.3*Vm –0.9*Dose)

17. Conditions Affection Phenytoin Condition or Disease Example Vmax increasedEnzyme inductionConcurrent phenobarb/Carbaz epine Vmax decreasedCirrhosisDecreased enzyme activity Km increasedCompetitive Inhibition Cimetidine or Chloramphenicol Km decreasedDecrease ProteinBinding Dec. albumin or displacers:Valproi c acid

18. Clinical Response and Side Effects Kutt H et al. Arch Neurol 1964; 11:642-48

19. Estimating the Loading Dose of Phenytoin LD= Vd (C desired – C observed)/S*F Where: Vd = volume of distribution ( 0.65L/kg) S=salt factor ( 0.92) F= fraction absorbed ( 1 ) Cdesired=10 to 20 mg/L Cobserved: if the patient is on phenytoin already and has a level prior to therapy

20. Estimating Maintenance Dose Mean Km for adults: 5.8 mg/L ( 0.1-27) and 5.3 mg/l for children Mean Vmax for adults:8mg/kg/day, children 12 mg/kg/day Dose/day= Vmax*Css/Km+Css

21. Estimating Maintenance Dose Based on one SS Phenytoin CP Vozeh S et al. J Pharmacokinet Biopharm 1981;9:131-46

22. Estimation of Dose based on two SS Phenytoin CP:Mullen Method Mullen RW. Clin Pharm Ther 1978;23:228-32

23. Estimation of Dose based on two SS Phenytoin CP:Ludden Method Ludden TM et al. Clin Pharm Ther 1977;21:287-93

24. Case Study #1 Mr SG is a 58 y/o, 72 inch, 70 kg male, seen recently with symptoms of a lower Respiratory infection. At this time he had a lesion noted on his Chest X-ray. A lung biopsy revealed a carcinoma with metastasis to The head, demonstrated via a CT scan. His albumin was 4 gm/l and serum creatinine 1.0.Phenytoin therapy was initiated prohylactically at a dosage of 400 mg daily. Two weeksLater the patient had a grand mal seizure and the phenytoin Cp was5 mg/l. The dosage was increased to 500 mg qd and 3 weeks laterThe phenytoin concentration was 7 mg/l.

25. Case # 1: Questions Using the Ludden method graph and estimate the Vmax and Km for this patient. Using this information, estimate a dose necessary to achieve a phenytoin concentration of 15 mg/l Given the Vmax and Km estimate the timeto 90% of steady state Estimate a Loading dose to achieve 15mg/l now.

26. Case 1: Using DrugCalc Using drugcalc, input the patient history, dosing history, and phenytoin history and model this See how Vmax and Km compare with the Ludden method.

27. Case 1 : Answers to Ludden Method DoseCpDose/CP

28. Ludden Example Y intercept=1225mg/day= Vmax Slope=11.6mg/l= Km Dose/day=Vmax xCp/Km+cp Dose/day=1225x15/11.6+15 Dose/day= 690mg phenytoin acid Dose/day=750 mg phenytoin sodium

29. Case 1 : Using Drugcalc Input the patient dosage/cp history and estimate Vmax and Km Using the Dosage calculator, estimate the dose to achieve a phenytoin concentration of 15 mg/L

30. Screen # 1 : Input the name/age After inputing the name and age click on accept

31. Choose phenytoin

32. Select Edit Demographics

33. Enter in the height, weight, serum albumin and serum creatinine When completed, click on accept

34. Select inpatient dosing

35. Insert Dose/Cp history Using the shortcut for multiple doses, 14s indicating 2 weeks, 21 s Indicating 3 weeks. D is for data ( concentration). ( s for sustained release) Click on add after entering each line. When complete click on accept

36. Choose Predict to Model : Select Parameters

37. Review the Vmax, Km, Vd Click on done when finished

38. Predicting SS dose Using the new vmax and Km and the equation for dose, reestimate, by hand the dose of phenytoin necessary to achieve a ss concentration of 15 mg/l